The article by Wunderink et al., like the original paper, is thoughtful and informative. However, the results are a bit surprising and will hopefully not encourage clinicians to discontinue maintenance antipsychotic treatment. My own view is that we should be taking relapse very seriously, as it may play a critical role in disease progression, in addition to the obvious associated psychosocial risks. An earlier Dutch cohort study with a 15-year follow-up found accruing morbidity and identified relapse as a critical factor. After each relapse, a subset of patients experienced persistence of positive and negative symptoms (Wiersma et al., 1998).

Given the very strong association between treatment discontinuation and relapse (Robinson et al., 1999), our inability to accurately identify early warning signs of relapse, and the failure of rescue medication to abort relapse, together with additional evidence for emergent treatment refractoriness in a subset of patients after relapse (Emsley et al., 2013), long-term maintenance treatment seems indicated.

While the empirical data on short-term studies of antipsychotics has produced considerable positive results, there is very little evidence on the long-term (four years or longer) efficacy of antipsychotics. Leucht and colleagues have noted “nothing is known about the effects of antipsychotic drugs compared to placebo after three years….” (Leucht et al., 2012).

Since multiyear (four years or longer) double-blind, drug-placebo studies of schizophrenia cannot be done, the relative lack of firm, long-term evidence on antipsychotic medications makes it more important that evidence from other types of studies be considered more carefully. This includes the long-term outcome of lower-dose and non-medicated schizophrenia patients from the seven-year Wunderink study and our 15- to 20-year naturalistic research finding more favorable long-term outcomes for unmedicated schizophrenia patients than those continuously prescribed antipsychotics (Harrow and Jobe, 2007; Harrow et al., 2012; Harrow and Jobe, 2013). The Wunderink research involves comparison of maintenance antipsychotic treatment with a randomly assigned dose reduction/discontinuation sample of patients with schizophrenia. The findings in favor of the lower dose/discontinuation sample from this research raise major questions about the efficacy of antipsychotics when they are used for long-term treatment.

Similar results emerged from multiple follow-ups across 15-20 years comparing our longitudinal sample of schizophrenia patients continuously prescribed (over the 15 to 20 years) antipsychotics with those not on antipsychotics for the last 15-20 years. In this research, the non-medicated patients functioned significantly better after the first two-year follow-up, and this continued thereafter, with these results also raising major questions about the longitudinal treatment of schizophrenia.

In addition, for schizophrenia patients on continuous antipsychotic medication, we found low rates of recovery (both functional and complete symptomatic recovery for a year or longer were required for the rating of recovery), a number of rehospitalizations, poor work functioning, and a surprising frequent presence of disrupted functioning. The differences between our sample of unmedicated patients with schizophrenia and our continuously medicated patients were significant starting at the 4.5-year follow-up and continuing up to 20 years. In general, prognostic measures we used indicted our unmedicated schizophrenia patients had a better prognosis, but even when this was controlled for, our continually prescribed patients had poorer outcomes. This longitudinal research raises issues of whether long-term treatment of schizophrenia with antipsychotics facilitates recovery and whether all, some, or very few schizophrenia patients benefit from a treatment plan involving continuous use of antipsychotics throughout their lifetimes.

In regard to the long-term evidence on the efficacy of antipsychotic medications, both the lower dose/discontinuation comparison with maintenance antipsychotics in the research of Wunderink and colleagues and our research comparing schizophrenia patients prescribed antipsychotics for 20 years with those not on antipsychotics for 20 years show a striking similarity. Both of these longitudinal programs found that the largest and most significant differences occurred on a long-term basis after the first two years.

While both of the above long-term research programs show samples of unmedicated or low-medicated schizophrenia patients in recovery, they are not unique. Research on other long-term samples from the Chestnut Lodge Study by Fenton and McGlashan (Fenton and McGlashan, 1987), the Vermont Long-Term Study by Harding (Harding et al., 1987), the World Health Organization Study and the DOSMED by Jablensky and many others (Jablensky and Sartorius, 2008), and M. Bleuler’s longitudinal sample (1978) all point to long-term samples of schizophrenia patients who show recovery. In our long-term 20-year sample, the periods of complete recovery varied in length, with some unmedicated schizophrenia patients showing complete recovery for a few years and others for a much longer period. In addition, schizophrenia patients who were continuously prescribed antipsychotics showed significantly fewer periods of complete recovery than those not prescribed antipsychotics at any follow-up (p Overall, based on multiple samples of schizophrenia patients from different countries, the positive evidence on some unmedicated samples of schizophrenia patients showing long-term favorable outcomes was overwhelming. The questions, of course, are what types of schizophrenia patients show favorable outcomes while unmedicated, how large a percentage show this, and, as McGorry and others have noted, what other types of interventions besides medications are helpful. In non-psychiatric areas, the original effectiveness of some medications continues for many years, but for other medications the body readjusts and they become less effective over time. The above studies alert us to the issue of whether multiyear treatment of schizophrenia patients with antipsychotics is helpful or harmful to many of these patients and to which ones. This important issue is still to be resolved with studies lasting longer than two to three years.

References:

Bleuler M. 1978. The Schizophrenic Disorders: Long-Term Patient and Family Studies. New Haven: Yale University Press.

This is an important contribution that has a number of important implications:

First, outcomes such as relapse and remission seem very crude to me, and they tell very little about what is of interest to many people with schizophrenia. An advantage of this study is that the authors used a sophisticated functional measure. I agree with Cenk Tek that patients who have a recurrence when the dose of antipsychotic is too low or medications have been stopped can become better managers of their illnesses (see Cenk Tek's full comment). I also believe that one of the goals of early treatment should be to educate patients to self-manage symptoms when they occur so that a minor exacerbation can be successfully managed.

Second, this study reminds us of an older literature from the 1980s, including my work (Marder et al., 1984), which documented that living with excessive dopamine blockade can be a personal burden that is associated with increased ratings of anxiety and depression that interfere with functioning. Other burdens of higher antipsychotic doses can include weight gain and sedation, which may interfere with adjustment.

Third, I agree with Will Carpenter that treatment of these individuals is likely to be optimal when patients and their treatment providers make decisions about drug doses and drug strategies in a collaborative atmosphere (see William Carpenter's full comment). According to Wunderink and co-authors, optimal treatment was more likely to occur in the drug reduction group.

Shortly after publishing a Cochrane review on intermittent drug techniques for schizophrenia (Sampson et al., 2013), we were pleased to see Lex Wunderink and colleagues publish these new findings from their five-year follow-up. This current review includes the initial data of Wunderink et al. from the two-year study demonstrating double the relapse rates in their dose-reduction strategy relative to the maintenance treatment group. These data must be considered within the totality of all similar evidence, or there is risk of overextrapolating results from small trials. However, along with five other important and pioneering trials, the two-year findings by Wunderink et al. are entirely consistent (I2 = 0 percent) with other results (RR Relapse 2.46 95 percent CI 1.7-3.5), with Wunderink and colleagues' data contributing 42 percent of the weight to the finding. At around two years, maintenance treatment does seem to avoid more relapses than a variety of intermittent drug strategies.

The review also suggests that intermittent treatment is significantly better than placebo in terms of relapse rates (2 RCTs, n = 290, RR 0.37 95 percent CI 0.24-0.58). This relates to Dr. Carpenter’s valid point on the earlier report from Wunderink et al. (see Carpenter's comment) that for many reasons, poor adherence to antipsychotic medication is common and that greater consideration of the types of people who may well benefit from a "targeted drug strategy" is required between clinicians and their patients. Although NICE guidelines state that low-dose prescribing and use of intermittent dosing strategies may well minimize side effects in the long-term use of antipsychotic medication, the risk of symptom worsening and relapse is stated to outweigh any benefits of the intermittent techniques "in the long term" (NICE, 2010).

Wunderink and colleagues' welcome new data, however, help bridge a gap in understanding the longer effects of such intermittent techniques on recovery after first-episode psychosis. It is good to see this long-neglected important area of research active after so long in hibernation. But, as Gaebel et al. and Wunderink et al. help us emerge from the permafrost, it is important to remember that Wunderink and colleagues' remarkable achievement in following people for so long is still results based on only 103 people. Psychiatry, blinking in the sunlight, has so often followed a good result full of hope. If replication is impractical, caution in consideration is vital—or the first swallow of summer may turn out to be the last hawk of winter.